2-169305709-G-C

Variant names:

• chr2-169305709-G-C
• rs830971
• NM_004525.3:c.427+1572C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000649046.1(LRP2):​c.427+1572C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 152,154 control chromosomes in the GnomAD database, including 3,302 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (3302 hom., cov: 32)
• Consequence: LRP2 ENST00000649046.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.588
• Publications: 4 publications found

Genes affected

LRP2 (HGNC:6694): (LDL receptor related protein 2) The protein encoded by this gene, low density lipoprotein-related protein 2 (LRP2) or megalin, is a multi-ligand endocytic receptor that is expressed in many different tissues but primarily in absorptive epithilial tissues such as the kidney. This glycoprotein has a large amino-terminal extracellular domain, a single transmembrane domain, and a short carboxy-terminal cytoplasmic tail. The extracellular ligand-binding-domains bind diverse macromolecules including albumin, apolipoproteins B and E, and lipoprotein lipase. The LRP2 protein is critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones. This protein also has a role in cell-signaling; extracellular ligands include parathyroid horomones and the morphogen sonic hedgehog while cytosolic ligands include MAP kinase scaffold proteins and JNK interacting proteins. Recycling of this membrane receptor is regulated by phosphorylation of its cytoplasmic domain. Mutations in this gene cause Donnai-Barrow syndrome (DBS) and facio-oculoacoustico-renal syndrome (FOAR).[provided by RefSeq, Aug 2009]

LRP2 Gene-Disease associations (from GenCC):

• Donnai-Barrow syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Stickler syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000649046.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.427+1572C>G		intron	N/A	NP_004516.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.427+1572C>G		intron	N/A	ENSP00000496870.1
	LRP2	ENST00000443831.1	TSL:2	c.427+1572C>G		intron	N/A	ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31097 AN: 152036 Hom.: 3300 Cov.: 32

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.0764

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.212

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.204 AC: 31111 AN: 152154 Hom.: 3302 Cov.: 32 AF XY: 0.205 AC XY: 15283 AN XY: 74374

African (AFR) AF: 0.238 AC: 9873 AN: 41496

American (AMR) AF: 0.166 AC: 2540 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 816 AN: 3472

East Asian (EAS) AF: 0.0764 AC: 396 AN: 5182

South Asian (SAS) AF: 0.184 AC: 888 AN: 4826

European-Finnish (FIN) AF: 0.240 AC: 2541 AN: 10580

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13513 AN: 67988

Other (OTH) AF: 0.211 AC: 445 AN: 2114

Alfa AF: 0.205 Hom.: 424

Bravo AF: 0.198

Asia WGS AF: 0.123 AC: 428 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.36
DANN	Benign	0.67
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs830971; hg19: chr2-170162219;